Neuropeptide Y restores appetite and alters concentrations of GH after central administration to endotoxic sheep

Abstract

The objective of this study was to determine whether neuropeptide Y (NPY) and recombinant human interleukin-1 receptor antagonist (IL-1ra) would: first, increase food intake; secondly, decrease concentrations of GH; thirdly, reduce GHRH-induced release of GH; and fourthly, reduce changes to concentrations of IGF-I in plasma during experimental endotoxemia in sheep.Six treatments were given to six castrated male sheep in a 6 6 Latin square treatment order. Osmotic minipumps were implanted at 0 h and a jugular vein was cannulated. Each sheep was continuously infused with saline (0·9%) or lipopolysaccharide (LPS) (20 µg/kg per 24 h, s.c.) at 10 µl/h for 72 h via the osmotic mini-pumps. Blood samples (3 ml) were collected at 15-min intervals from 24 to 33 h. At 26 h, one of three treatments (artificial cerebrospinal fluid, NPY or IL-1ra) was injected i.c.v. within 30 s (0·3 µg/kg), then infused i.c.v. from 26 to 33 h (600 µl/h) at 0·3 µg/kg per h. GHRH was injected i.v. (0·075 µg/kg) at 32 h after which blood samples were collected at 5, 10, 15, 30, 45 and 60 min. Feed intake was reduced up to 50% for 48 h in LPS-treated compared with non-LPS-treated sheep.NPY restored feed intake in LPS-treated sheep and induced hyperphagia in non-LPS-treated sheep from 24 to 48 h. In contrast, IL-1ra did not affect appetite. Injection of NPY increased concentrations of GH from 26 to 27 h, while IL-1ra had no effect. Infusion of NPY suppressed GHRH-induced release of GH. However, no treatment altered pulse secretion parameters of GH. Concentrations of IGF-I were 20% higher at 72 h in LPS-treated sheep given NPY than in sheep treated with LPS alone, and this may reflect increased appetite from 24 to 48 h.We concluded that reduced appetite during endotoxemia is due to down-regulation of an NPY-mediated mechanism. Furthermore, NPY stimulates release of GH in healthy sheep, does not reduce pulse secretion parameters of GH, but does suppress GHRH-induced release of GH in endotoxic sheep. Therefore, NPY may be an important neurotransmitter linking appetite with regulation of GH during endotoxemic and healthy states in sheep.

Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep

“…In an interesting study linking appetite to the growth axis, growth hormone-releasing hormone was found to colocalize with NPY in the ARC during periods of undernutrition . Moreover, NPY is a known stimulus to GH release in sheep (McMahon et al, 1999;Morrison et al, 2003) and cattle (Thomas et al, 1999) and an inhibitor of LH , suggesting that the effects of fasting may be linked to GH and LH by way of the NPY neuron.…”

“…This effect of NPY to increase feed intake was also significant in the presence of rumen distention or propionate infusion (Miner et al, 1990). In a related study, endotoxin was used to inhibit feed intake in sheep (as a model for disease) and was coupled with NPY infusion ICV (McMahon et al, 1999). The infusion of NPY in continually endotoxin-treated sheep normalized feed intake during the period of infusion.…”

“…In an interesting study linking appetite to the growth axis, growth hormone-releasing hormone was found to colocalize with NPY in the ARC during periods of undernutrition . Moreover, NPY is a known stimulus to GH release in sheep (McMahon et al, 1999;Morrison et al, 2003) and cattle (Thomas et al, 1999) and an inhibitor of LH , suggesting that the effects of fasting may be linked to GH and LH by way of the NPY neuron.Fetal sheep also express NPY within the hypothalamus at least by day 110 of gestation, which led to an interesting hypothesis that fetal nutrition may imprint on developing neural circuitry in the hypothalamus and have serious consequences in later life (Mü lhaü sler et al, 2004). The role of fetal NPY was further illustrated by lateral ventricle injections of NPY into fetal sheep, which resulted in increased swallowing behavior (El-Haddad et al, 2003).…”

A Role for Agouti-Related Protein in Appetite Regulation in a Species with Continuous Nutrient Delivery

“…For example, in fasted rodents, growth hormone (GH) concentrations decrease [12], whereas they increase in other species such as sheep [13]and humans [14]. Interestingly, in the rat, GH concentrations are reduced by NPY [15], while NPY increases GH in sheep [16]. Furthermore, sheep have fewer projections extending from the arcuate nucleus to the paraventricular nucleus as compared with the number of projections from the arcuate nucleus to the preoptic area and the bed nucleus of the stria terminalis, a pattern which differs from that found in the rodent [17].…”

Neuropeptides and the Microbiota-Gut-Brain Axis

“…NPY is involved in the regulation of emotional-affective behaviour [6,[81][82][83][84], and there is indirect evidence that NPY-expressing neurons in the arcuate and paraventricular nuclei of the hypothalamus counteract the behavioural responses to immune stress and infection [109][110][111]. This implication has been confirmed by knockout experiments in which the NPY/Y receptor system has been found to protect against distinct functional disturbances in response to immune challenge.…”